Liposomal encapsulation of local anesthetics has been shown to increase the duration of pain relief. Critical factors in the effectiveness of liposomal bupivacaine formulations include encapsulation of the maximal amount of drug, as well as a suitable release rate after injection. The primary disadvantages of previously described liposomal bupivacaine formulations (e.g. Boogaerts, Grant, Legros) are relatively inefficient drug entrapment and low drug/lipid ratios. This can lead to an undesirable deposit of fatty lipid material at the site of injection.
Recently, active loading of bupivacaine using a pH gradient was described (Mowat). A sodium citrate solution was used to establish a transmembrane gradient, and a drug/lipid ratio of 0.26 was achieved, higher than that obtained previously via standard “passive” loading techniques (e.g. Legros). However, in Mowat, the extraliposomal pH was maintained at about 7.4, which potentially limits the amount of drug available for loading, as bupivacaine is poorly soluble at this pH.